Osteocytes comprise 90% of all bone cells, yet little is known of their function(s) or of the involvement of systemic hormones in regulating their activity. These cells occupy lacunae deep within the mineralized matrix of bone and communicate with one another and with osteoblasts via gap junctions. We have recently reported that osteocytes express high level of receptor that specifically recognizes the carboxyl(C)-terminal portion of PTH, the CPTH receptor. These cells derived from genetically altered mice that lack the PTH1R and ubiquitously express an immortalizing SV40 T-antigen that allows the establishment of conditionally immortalized cells lines. In preliminary studies we have isolated and characterized three osteocytic cell lines that appear to express very high CPTHRs. In these cells activation of the CPTHRs was able to induce apoptosis as well increase the amount of connexin 43. In addition, we also demonstrated the presence of CPTHRs on osteoclasts and osteoclast precursors. It appears that, unlike the PTH1R, this novel receptor is expressed also on the surface of hematopoietic cells in the bone marrow, where is can affect the number of mature osteoclasts, possibly by modulating proliferation, differentiation, fusion or survival of these cells. This project will address two main aims: PTH regulation of apoptosis in osteocytes, and the effect of CPTHRs activation on osteoclasts. The first aim is directed towards understanding the molecular mechanisms underlying the proapoptotic effect of CPTH fragments on osteocytes and the potential functional interaction of PTH1R and CPTHR activation in these cells. The second aim is focused on the analysis of the mechanisms of action of CPTHRs on osteoclasts and osteoclast precursors. These studies will provide new insight into osteocytes and osteoclasts function and of the role of intact, N-terminal and C-terminal PTH in regulating their behavior.